Kuykendall's first involvement with Republican politics came in 1960, when he volunteered for the Richard Nixon campaign. He first came to attention two years later, when he managed former city councilman Ed Davis' campaign for Congress in the Memphis-based 9th Congressional District. In that race, Davis came within only 1,200 votes of defeating 22-year incumbent Clifford Davis. In 1963 and 1964, he served as a co-chairman of the Shelby County Republican Party,[1] which was returning to prominence after years of irrelevance. This was largely due to a massive crossover of white voters to the Republicans—the same factor which fueled Davis' near-upset in 1962.[citation needed]

In 1964 he won the Republican nomination for United States Senate and ran against incumbent Democrat Albert Gore, Sr. Kuykendall was initially given little chance against Gore. For most of the 20th century, the Republican Party had been practically nonexistent outside of traditionally heavily Republican East Tennessee, and most statewide races were decided in the Democratic primary. However, Kuykendall ran a surprisingly competitive race, taking 46 percent of the vote to Gore's 53 percent—the closest a Republican had come to winning a full term in the Senate since Reconstruction. The margin would have almost certainly been closer than that if not for the massive landslide, both nationally and in Tennessee, by PresidentLyndon Johnson over Barry Goldwater.

Kukyendall's strong showing in the Senate race made him very popular in Tennessee Republican circles. In 1966, Kuykendall rode this momentum to win the Republican nomination for the 9th District. Taking advantage of the large crossover of white voters, he narrowly defeated freshman Democratic Congressman George W. Grider in November, becoming the first Republican congressman from West Tennessee since 1883. Kuykendall soon established himself as one of the House's most conservative members. He was also known for being long-winded to the point of what many felt was verbosity, and as a consequence was given the somewhat derisive nickname "The Tennessee Talking Horse".

Kuykendall became very popular in his district, even though most of its living residents had never been represented by a Republican before. He skated to reelection in 1968 and 1970. However, reapportionment based on the 1970 federalcensus caused Tennessee to lose a congressional district. In an attempt to punish neighboring 6th District Congressman William Anderson for his perceived liberalism and national ambitions, the General Assembly shifted several portions of Kuykendall's district, which was renumbered the 8th District, to the 6th. In return, several heavily Democratic and predominantly black areas near Memphis were shifted to the 8th, giving Kuykendall a larger proportion of blacks than he had previously represented. Kuykendall won re-election in 1972 against black pastor J. O. Patterson, Jr. in the midst of the national Republican landslide (in which Richard Nixon won 90 of Tennessee's 95 counties). Just after Kuykendall was sworn in for a fourth term, however, a near-violent reaction to a busing order prompted many whites to leave Memphis for the suburbs. These two events seriously eroded Kuykendall's base, and caused many analysts to speculate that the 8th wouldn't stay Republican for long.

In 1974, the Democrats nominated State RepresentativeHarold Ford, a young member of a prominent black funeral-directing family in Memphis whose political involvement dated to the days of E. H. Crump. Ford staged a tremendous get-out-the-vote campaign in the Memphis black community. He also received the support of many whites angered by Kuykendall's continued support of Nixon in the midst of Watergate; he had been one of the few Republicans who supported Nixon even after the release of the "smoking gun" transcripts.

On election night, it looked like Kuykendall had managed to hold onto the seat by a razor-thin margin. However, Ford's supporters found eight ballot boxes purported to have been in the dumpster of the then all-white Shelby County Election Commission. When those ballots were counted, it was enough for Ford to unseat Kuykendall by only 744 votes—one of the closest races of the 1974 cycle. Since then, Republicans have never come close to retaking the Memphis-area district. The district was renumbered the 9th District again in the 1980s round of redistricting, as Tennessee regained a House seat due to its population now growing at a rate above, rather than below, the national average. At that time, it was drawn as a majority-black district, and Republicans have lost interest in the seat.